PROJECT SUMMARY The long-term objective of the proposed research is to develop a safe and effective treatment for ovarian cancer with estimated prevalence of 167,000 patients in the USA. In >55% of patients, ovarian cancer recurs within two years after the first-line chemotherapy and the second and third line therapies are generally ineffective and toxic. This proposal describes a novel approach to cancer treatment that involves stimulation of patient's immune system against cancer-an interleukin-12 (IL-12) gene plasmid, formulated with a biocompatible polymer delivery system, is administered intraperitoneally to increase IL-12 concentrations locally for several days, or more, after each injection. IL-12 is a potent anticancer cytokine that works by activating patient's immune system and by also inhibiting tumor blood supply. The clinical proof of concept of the intended use of intraperitoneal IL-12 therapy (also called EGEN-001) has been demonstrated in two human Phase I clinical trials. In human Phase I clinical trials (partially supported by an Orphan Drug Grant Award 1R01 FD 003374-01), repeated administration of intraperitoneal EGEN-001, alone or in combination with chemotherapeutic agents, in recurrent ovarian cancer patients, resulted in good safety, biological activity, encouraging efficacy and recommendation by the clinical advisory board of an optimal dose and dosing frequency for future development. The specific aim of the proposed Phase II trial is to determine the efficacy and safety of long treatment cycles of EGEN-001 IP in platinum-resistant recurrent ovarian cancer patients. Primary end points include progression-free survival for at least 6 months, objective tumor response and frequency and severity of adverse effects. The ability to treat persistent ovarian cancer patients chronically with a safe and effective immunotherapeutic drug offers a new treatment paradigm for this chronic disease where effective treatment options are limited due to toxicity and drug resistance. The proposed study will be conducted at nationally recognized clinical centers of the Gynecological Oncology Group (GOG), a cooperative group of the National Cancer Institute. GOG has approved conducting the study in conjunction with EGEN. A Phase II protocol (DTM 0835) is under development at GOG.